Combinations of hydroxy-substituted azetidinone compounds and HMG CoA Reductase Inhibitors

- Schering Corporation

Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 and Ar.sup.2 are aryl or R.sup.4 -substituted aryl;Ar.sup.3 is aryl or R.sup.5 -substituted aryl;X, Y and Z are --CH.sub.2 --, --CH(lower alkyl)-- or --C(dilower alkyl)--;R and R.sup.2 are --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 or --O(CO)NR.sup.6 R.sup.7 ;R.sup.1 and R.sup.3 are H or lower alkyl;q is 0 or 1; r is 0 or 1; m, n and p are 0-4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1-6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1-5;R.sup.4 is selected from lower alkyl, R.sup.5, --CF.sub.3, --CN, --NO.sub.2 and halogen;R.sup.5 is selected from --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.sup.7, --(lower alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6 ;R.sup.6, R.sup.7 and R.sup.8 are H, lower alkyl, aryl or aryl-substituted lower alkyl;R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl;are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, pharmaceutical compositions containing them, and a process for preparing them.

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Claims

1. A pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising an effective amount of a compound represented by the formula I ##STR56## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of aryl and R.sup.4 -substituted aryl;

Ar.sup.3 is aryl or R.sup.5 -substituted aryl;
X, Y and Z are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)-- and --C(dilower alkyl)--;
R and R.sup.2 are independently selected from the group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 and --O(CO)NR.sup.6 R.sup.7;
R.sup.1 and R.sup.3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1; r is or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
R.sup.4 is 1-5 substituents independently selected from the group consisting of lower alkyl, --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.sup.7, --(lower alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN, --NO.sub.2 and halogen;
R.sup.5 is 1-5 substituents independently selected from the group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2)l 5OR.sup.6, --O(CO)N R.sup.6 R.sup.7, --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.sup.7, --(lower alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6;
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl;

2. A pharmaceutical composition of claim 1 wherein, in the compound of formula I, Ar.sup.1 is phenyl or R.sup.4 -substituted phenyl, wherein R.sup.4 is halogen; Ar.sup.2 is phenyl or R.sup.4 -substituted phenyl, wherein R.sup.4 is halogen or --OR.sup.6, wherein R.sup.6 is lower alkyl or hydrogen; Ar.sup.3 is R.sup.5 -substituted phenyl, wherein R.sup.5 is --OR.sup.6, wherein R.sup.6 is lower alkyl or hydrogen; X, Y, and Z are each --CH.sub.2 --; R.sup.1 and R.sup.3 are each hydrogen; R and R.sup.2 are each --OR.sup.6, wherein R.sup.6 is hydrogen; and the sum of m, n, p, q and r is 2, 3 or 4.

3. A composition of claim 1 wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin.

6. A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising administering to a mammal in need thereof an effective amount of a compound represented by the formula I ##STR57## or a pharmaceutically acceptable salt thereof, wherein: Ar.sup.1 and Ar.sup.2 are independently selected from the group consisting of aryl and R.sup.4 -substituted aryl;

Ar.sup.3 is aryl or R.sup.5 -substituted aryl;
X, Y and Z are independently selected from the group consisting of --CH.sub.2 --, --CH(lower alkyl)-- and --C(dilower alkyl)--;
R and R.sup.2 are independently selected from the group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9 and --O(CO)NR.sup.6 R.sup.7;
R.sup.1 and R.sup.3 are independently selected from the group consisting of hydrogen, lower alkyl and aryl;
q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5;
R.sup.4 is 1-5 substituents independently selected from the group consisting of lower alkyl, --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, --NR.sup.6 (CO) R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.sup.7, --(lower alkylene)COOR.sup.6, --CH.dbd.CH--COOR.sup.6, --CF.sub.3, --CN, --NO.sub.2 and halogen;
R.sup.5 is 1-5 substituents independently selected from the group consisting of --OR.sup.6, --O(CO)R.sup.6, --O(CO)OR.sup.9, --O(CH.sub.2).sub.1-5 OR.sup.6, --O(CO)NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, --NR.sup.6 (CO)R.sup.7, --NR.sup.6 (CO)OR.sup.9, --NR.sup.6 (CO)NR.sup.7 R.sup.8, --NR.sup.6 SO.sub.2 R.sup.9, --COOR.sup.6, --CONR.sup.6 R.sup.7, --COR.sup.6, --SO.sub.2 NR.sup.6 R.sup.7, S(O).sub.0-2 R.sup.9, --O(CH.sub.2).sub.1-10 --COOR.sup.6, --O(CH.sub.2).sub.1-10 CONR.sup.6 R.sup.7, --(lower alkylene)COOR.sup.6 and --CH.dbd.CH--COOR.sup.6;
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R.sup.9 is lower alkyl, aryl or aryl-substituted lower alkyl; in combination with an effective amount of a cholesterol biosynthesis inhibitor selected from the group consisting of HMG CoA reductase inhibitors.

7. A method of claim 6 wherein, in the compound of formula I, Ar.sup.1 is phenyl or R.sup.4 -substituted phenyl, wherein R.sup.4 is halogen; Ar.sup.2 is phenyl or R.sup.4 -substituted phenyl, wherein R.sup.4 is halogen or --OR.sup.6, wherein R.sup.6 is lower alkyl or hydrogen; Ar.sup.3 is R.sup.5 -substituted phenyl, wherein R.sup.5 is --OR.sup.6, wherein R.sup.6 is lower alkyl or hydrogen; X, Y, and Z are each --CH.sub.2 --; R.sup.1 and R.sup.3 are each hydrogen; R and R.sup.2 are each --OR.sup.6, wherein R.sup.6 is hydrogen; and the sum of m, n, p, q and r is 2, 3 or 4.

8. A method of claim 6 wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin.

Referenced Cited
U.S. Patent Documents
4375475 March 1, 1983 Willard et al.
4983597 January 8, 1991 Yang et al.
5099034 March 24, 1992 Yoshida
5350868 September 27, 1994 Yoshida
5631365 May 20, 1997 Rosenblum et al.
5661145 August 26, 1997 Davis
Foreign Patent Documents
199630 October 1986 EPX
264231 April 1988 EPX
337549 October 1989 EPX
93/02048 February 1993 WOX
WO94/17038 August 1994 WOX
Other references
  • Ram et al, Indian J. Chem., Sect B, 29B, 12 (1990), pp. 1134-1137. Hoekman et al, J. Agric. Food Chem., 30 (1982), pp. 920-924. Durst et al, Can. J. Chem., 50 (1972), pp. 3196-3201. Otto et al, Liebigs Ann. Chem., (1983), pp. 1152-1161. Panfil, et al., Heterocycles, 24, 6 (1986), pp. 1609-1617. Schnitzer-Polokoff, et al, Comp. Biochem. Physiol., 99A (1991), pp. 665-670. Witzum, Circulation, 80, 5 (1989), pp.1101-1114. Illingworth, Drugs, 36(Supp. 3) (1988), pp. 63-71. Allain, et al., Clin. Chem., 20, (1974), pp. 470-475. Horie, et al, Atherosclerosis, 88 (1991), pp. 183-192. Baxter, er al, J. Biological Chem., 267, 17 (1992), pp. 11705-11708. Current Drugs: Anti-Atheroscierotic Agents--Summary Factfile, May, 1992. Georg et al, Tet. Letters, 26, 45 (1985), pp. 3903-3906. Hart et al, Tet. Letters, 26, 45 (1985), pp. 5493-5496.
Patent History
Patent number: 5846966
Type: Grant
Filed: Oct 14, 1997
Date of Patent: Dec 8, 1998
Assignee: Schering Corporation (Kenilworth, NJ)
Inventors: Stuart B. Rosenblum (West Orange, NJ), Sundeep Dugar (Bridgewater, NJ), Duane A. Burnett (Fanwood, NJ), John W. Clader (Cranford, NJ), Brian A. McKittrick (Bloomfield, NJ)
Primary Examiner: Kimberly Jordan
Attorney: Anita W. Magatti
Application Number: 8/953,825